The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
Skin ageing is a dynamic process which is effected not only by intrinsic cellular and extracellular alterations over the passage of time but also by environmental, or extrinsic, factors such as inadequate nutrition, smoking, excessive alcohol consumption and particularly, chronic exposure to UV radiation.
Intrinsic, or chronological cutaneous aging is the result of inherent degeneration of connective tissue of the dermis. This form of skin aging is inevitable, although genetic influences may retard its onset and/or clinical progression. Instrinsically aged skin is manifested by epidermal and dermal atrophy, flattening of the epidermal rete ridge as well as decreased numbers of fibroblasts and mast cells and decreased levels of collagen. This is cosmetically characterized by a generally unblemished appearance but with fine lines, creases and loss of elasticity. (Baumann, L, 2007; Helfrich, Y. R, 2008; and references cited therein).
Photo-aging, a common causative factor in extrinsic aging, is the term used to describe the cosmetic and physiological effects of long-term exposure of the skin to environmental or artificial UV radiation. Whilst photo-aging can occur on any part of the body which is exposed to UV radiation, it occurs most commonly on the face, arms, hands, neck and upper chest. Photo-aged skin is manifested by an increase in the epidermal thickness or epidermal atrophy and most notably by solar elastosis, the accumulation of elastin-containing material just below the dermal-epidermal junction. Collagen and elastic fibres become fragmented and disorganized. At a cosmetic level this can be observed as a reddening and/or thickening of the skin (resulting in a leathery appearance), skin fragility and irregular pigmentation, loss of tone and elasticity (Baumann, L, 2007; Helfrich, Y. R, 2008; and references cited therein) as well as wrinkling, dryness, sunspots and deep furrow formation.
Hyaluronan, or hyaluronic acid (HA), is a high molecular weight (1×104-1×107 Da) non-sulfated polysaccharide component of the glycosaminoglycan family and is an important component of the dermal extracellular matrix (ECM), performing many pivotal structural and physiological functions. It consists of repeating disaccharide units of the sugars N-acetylglucosamine and D-glucuronic acid and is synthesized by HA synthase enzymes (HAS) of which three vertebrate genes have been isolated and characterized as HAS1, HAS2, and HAS3. Hyaluronan can bind up to 1000 times its weight in water and, together with other glycosaminoglycans (GAGs) helps the skin retain and maintain water, thereby maintaining a smooth, plump appearance. It is found in both the dermis and epidermis, particularly epidermal intercellular spaces, and is produced mainly by fibroblasts and keratinocytes.
Embryonic/early gestational foetal skin, the archetypical non-chronologically-aged/non-photo-aged skin, is characterized by elevated hyaluronan levels. In foetal skin it enhances collagen lattice reorganization and enhances the synthesis of collagen types III and V and in young skin, hyaluronan is found at the periphery of collagen and elastin fibres and where these intersect. In contrast, aged skin is characterized by de creased levels of hyaluronan and photo-aged skin has also been observed to exhibit reduced levels of hyaluronan. (Baumann, L., 2007 and references cited therein).
The increased hyaluronan levels associated with non-chronologically-aged/non-photo-aged skin, has been attributed to increased hyaluronan synthase (HAS) gene expression. It is commonly accepted that three HAS genes are responsible for the regulation of hyaluronan synthase; HAS1, HAS2 and HAS3. HAS1 gene expression is absent from non-aged/non-photo-aged fibroblasts. HAS2 is recognized as being essential to embryonic/foetal development and HAS3 is associated with chronologically-aged/photo-aged skin.
Hyaluronan molecular weight (in conjunction with concentration), is also important in influencing skin architecture, with high molecular weight hyaluronan forming a more effective pericellular coat than low molecular weight hyaluronan (Meran et al, 2007, 2008; Stern and Maibach, 2008). Indeed, the molecular weight of newly-synthesized hyaluronan in human skin is of high molecular weight, in both the epidermis and dermis. Whilst HAS1 and HAS3 are associated with the synthesis of lower molecular weight hyaluronan and as described above are associated with aged/photo-aged skin, HAS2-derived hyaluronan is of high molecular weight (typically at least 1.5×106 Da).
Although it is widely acknowledged that the best and most effective way of preventing, or at least minimizing, the photo-aging process is avoidance of exposure of the skin to UV radiation, namely staying out of the sun and wearing protective clothing and sunscreen, the intrinsic aging process is inevitable and there nevertheless remains a strong demand in today's youth-obsessed society for treatments which can “turn back the clock” by reversing or at least improving or ameliorating one or more of the cosmetic manifestations of the chronological-aging and/or photo-aging process such as lines, wrinkles, dryness, furrows, reddening, thickening, sunspots, loss of tone and elasticity, fragility, and irregular pigmentation. Indeed, consumer demand for cosmetic agents which can restore a youthful appearance to chronologically-aged or photo-aged skin, particularly facial skin, is ever increasing, with the anti-aging market expected to reach over $16.5 billion in sales by 2010 in the United States alone (Helfrich, Y. R., et al, 2008).
Given this demand, there remains a need for new treatments which may assist in reversing, improving or otherwise ameliorating one or more of the cosmetic manifestations associated with chronological-aging and photo-aging of skin.